tetano
Editor, Senior Moderator
J Med Chem. 2018 Jul 20. doi: 10.1021/acs.jmedchem.8b00557. [Epub ahead of print]
[h=1]From naproxen repurposing to naproxen analogues and their antiviral activity against Influenza A virus.[/h] Dilly S, Fotso Fotso A, Lejal N, Zedda G, Chebbo M, Rahman F, Companys S, Bertrand HC, Vidic J, Noiray M, Alessi MC, Tarus B, Quideau S, Riteau B, Slama-Schwok A.
[h=3]Abstract[/h] The nucleoprotein (NP) of Influenza A virus (IAV) required for IAV replication, is a promising target for new antivirals. We previously identified by in silico screening naproxen being a dual inhibitor of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory effects. However, the recently shown strong COX2 antiviral potential makes COX2 inhibition undesirable. Here we designed and synthesized two new series of naproxen analogues called derivatives 2, 3 and 4 targeting highly conserved residues of the RNA binding groove, stabilizing NP monomer without inhibiting COX2. Derivative 2 presented improved antiviral effects in infected cells compared to that of naproxen, and afforded a total protection of mice against a lethal viral challenge. Derivative 4 also protected infected cells challenged with circulating 2009-pandemic and oseltamivir-resistant H1N1 virus. This improved antiviral effect likely results from derivatives 2 and 4 inhibiting NP-RNA and NP-polymerase acidic subunit PA N-terminal interactions.
PMID: 30028133 DOI: 10.1021/acs.jmedchem.8b00557
[h=1]From naproxen repurposing to naproxen analogues and their antiviral activity against Influenza A virus.[/h] Dilly S, Fotso Fotso A, Lejal N, Zedda G, Chebbo M, Rahman F, Companys S, Bertrand HC, Vidic J, Noiray M, Alessi MC, Tarus B, Quideau S, Riteau B, Slama-Schwok A.
[h=3]Abstract[/h] The nucleoprotein (NP) of Influenza A virus (IAV) required for IAV replication, is a promising target for new antivirals. We previously identified by in silico screening naproxen being a dual inhibitor of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory effects. However, the recently shown strong COX2 antiviral potential makes COX2 inhibition undesirable. Here we designed and synthesized two new series of naproxen analogues called derivatives 2, 3 and 4 targeting highly conserved residues of the RNA binding groove, stabilizing NP monomer without inhibiting COX2. Derivative 2 presented improved antiviral effects in infected cells compared to that of naproxen, and afforded a total protection of mice against a lethal viral challenge. Derivative 4 also protected infected cells challenged with circulating 2009-pandemic and oseltamivir-resistant H1N1 virus. This improved antiviral effect likely results from derivatives 2 and 4 inhibiting NP-RNA and NP-polymerase acidic subunit PA N-terminal interactions.
PMID: 30028133 DOI: 10.1021/acs.jmedchem.8b00557